Adv Sci (Weinh). 2026 Apr 3:e17640. doi: 10.1002/advs.202517640. Online ahead of print.

ABSTRACT

The embryonic coelomic mesothelium acts as a critical progenitor hub during mammalian organogenesis, undergoing epithelial-to-mesenchymal transition (EMT) to drive vascular growth and parenchymal development in visceral organs. A prominent example is the epicardium, which plays an essential role during heart development. The principles of gene regulation in the coelomic mesothelium remain poorly defined. Specifically, it is unclear how cis-regulatory elements, including enhancers, orchestrate the spatiotemporal patterns of gene expression required for mesothelial identity and function. Here, a multi-omic approach was used to identify trans- and cis-regulatory elements that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. This analysis uncovers a cardiac-specific regulatory circuit in which the transcription factor (TF) TBX20 selectively activates epicardial enhancers to orchestrate essential developmental programs. In contrast, TF MAF orchestrates pan-mesothelial gene expression via conserved CREs, which are absent in non-mesothelial lineages. Our integrated genomic analysis reveals MAF as a central custodian of mesothelial identity, a role underscored by its negative correlation with EMT, evolutionary conservation, and dynamic regulatory activity throughout development. Our work establishes a foundational blueprint of the gene regulatory landscape governing the coelomic mesothelium, defining both conserved principles and organ-specific mechanisms of spatiotemporal gene expression during early mammalian development.

PMID:41933934 | DOI:10.1002/advs.202517640

Future Sci OA. 2026 Dec;12(1):2653101. doi: 10.1080/20565623.2026.2653101. Epub 2026 Apr 3.

ABSTRACT

BACKGROUND: Clarification of the molecular mechanism of malignant tumor progression, identification of the key signaling pathways and molecules involved in the processes of invasion and metastasis, and identification of new targets and strategies for effective tumor treatment are extremely important for scientific research and clinical application prospects.

METHODS: Based on large-sample data mining, we first evaluated the expression and mutation profiles of SPRR family genes across cancers and then focused on the molecular functions of SPRR2D across cancers.

RESULTS: Multi-omics experiments revealed that SPRR2D is significantly overexpressed in various tumors, especially in LUSC. ROC curve analysis revealed that SPRR2D demonstrated significant diagnostic efficacy across cancers. Cox regression analysis revealed that the expression of SPRR2D was associated with the survival time of patients with various tumors. Moreover, the expression of SPRR2D is closely related to tumor immune infiltration. GDSC data analysis revealed that the expression levels of SPRR1A, SPRR1B, SPRR2A, SPRR3, and SPRR2D are negatively correlated with the sensitivity to gefitinib, trametinib, bosutinib, afatinib, lapatinib, and erlotinib.

CONCLUSIONS: From a multi-omics perspective, it was revealed that SPRR2D plays a significant role in regulating tumorigenesis and drug sensitivity in tumors.

PMID:41933926 | PMC:PMC13051589 | DOI:10.1080/20565623.2026.2653101

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

J Intern Med. 2026 Apr 3. doi: 10.1111/joim.70092. Online ahead of print.

ABSTRACT

Tuberculosis (TB) remains a major global health challenge, with multi-drug antibiotic regimens as the current standard of care. While effective at killing Mycobacterium tuberculosis, these treatments do not resolve persistent inflammation, prevent lung damage, or reverse immune dysregulation that contribute to poor outcomes and disease recurrence. Precision medicine offers a promising alternative but requires deeper insight into disease mechanisms to enable tailored interventions. This comprehensive review introduces the concept of immune endotyping to define the underlying disease mechanisms as tools to decode clinical and immunological heterogeneity in TB. TB displays a wide spectrum of clinical phenotypes, from latent or asymptomatic infection to mild or severe disease with characteristic non-cavitary or cavitary lung pathology. Instead, distinct immune endotypes capture the diverse biological pathways that shape disease progression and treatment response. Similar clinical presentations may arise from different immune dysfunctions, underscoring the need to move beyond broad phenotypic classifications. Advances in multi-omics and computational analyses uncover immune signatures that enable stratification for host-directed therapies (HDTs) targeting hyperinflammation, immunosuppression, coagulopathy or metabolic exhaustion. Integrating clinical, radiological, and immunological data through multimodal profiling is essential for developing personalized interventions. We also explore how endotyping has transformed treatment in other diseases, offering valuable insights for TB. Additionally, we present examples of how putative immune endotypes may be targeted with appropriate HDTs. In summary, this review underscores the potential of immune endotypes to advance precision medicine in TB, moving beyond one-size-fits-all treatment to improve outcomes, especially in severe and drug-resistant cases.

PMID:41930636 | DOI:10.1111/joim.70092

Oncol Res. 2026 Mar 23;34(4):11. doi: 10.32604/or.2026.076176. eCollection 2026.

ABSTRACT

Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8⁺ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

PMID:41930159 | PMC:PMC13040304 | DOI:10.32604/or.2026.076176

Oncogenesis. 2026 Apr 2. doi: 10.1038/s41389-026-00603-7. Online ahead of print.

ABSTRACT

Gallbladder cancer (GBC) is an aggressive malignancy characterized by metabolic plasticity and profound immune evasion. However, the functional role of glutathione peroxidase 3 (GPX3), a secreted antioxidant enzyme, in these processes remains unclear. Multi-omics analyses of paired GBC and adjacent non-tumor tissues revealed consistent downregulation of GPX3, which correlated with reactive oxygen species (ROS) accumulation and enhanced glycolytic activity. Functional restoration of GPX3 in GBC cells reduced intracellular ROS levels, suppressed the expression of glycolysis-related enzymes, and consequently impaired tumor proliferation, migration, and invasion. In xenograft models, GPX3 overexpression markedly attenuated tumor growth and lung metastasis. Notably, GPX3 restoration also enhanced CD8⁺ T cell infiltration and elevated pro-inflammatory cytokine production, suggesting reversal of tumor-associated immunosuppression. These findings identify GPX3 as a critical tumor suppressor that integrates redox regulation, metabolic reprogramming, and immune activation to restrict malignant progression. Targeting GPX3 or its downstream pathways may represent a promising therapeutic strategy to simultaneously suppress gallbladder cancer aggressiveness and reinforce anti-tumor immunity.

PMID:41927557 | DOI:10.1038/s41389-026-00603-7

Curr Comput Aided Drug Des. 2026 Mar 31. doi: 10.2174/0115734099433388260204214424. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. BI-1015550 is an oral phosphodiesterase 4B (PDE4B) inhibitor that has shown anti-inflammatory and anti-fibrotic effects; the exact molecular target(s) and mechanism of action in fibrosis are unknown. BI-1015550, an orally available PDE4B inhibitor with a possible anti-fibrotic effect, whose molecular mechanism of action is unknown Methods: We adopt an integrative approach that combines network pharmacology for identifying putative targets, molecular docking, and Molecular Dynamics (MD) simulations to assess the binding, ML-based target prioritization. Predicted targets/pathways were verified by Western blotting and Immunohistochemistry (IHC).

RESULTS: Network pharmacology analysis identified eight key targets: PTGS2, VCAM1, MMP1, IGF1, MMP7, CCL5, MMP13, and SELE. Docking results and MD simulation demonstrated that the predicted major targets of BI-1015550 include MMP1, PTGS2, and VCAM1. Therapeutic targets were also prioritized using machine learning methods. BI-1015550 treatment significantly decreased collagen deposition and HYP content of lung tissues in vivo. It down-regulated PTGS2, MMP1, and VCAM1 proteins via modulation of the NF-κB signaling pathway.

DISCUSSION: We presented an integrative multi-omics approach based on in silico prediction and wet-lab experiments to dissect the antifibrotic activity of BI-1015550. We showed here that BI- 1015550 mainly acts by inhibiting the NF-κB axis, resulting in downstream suppression of profibrotic and proinflammatory mediators. Our work on integrating network pharmacology with molecular simulation and ML is promising in both identifying reliable targets and providing a solid basis for further drug repurposing and mechanistic investigations. The better performance of BI-1015550 than current drugs (i.e., nintedanib and pirfenidone) demonstrates that it could be considered as an effective multi-target therapy against IPF.

CONCLUSION: BI-1015550 attenuates idiopathic pulmonary fibrosis through the suppression of the NF-kB signalling pathway and up-regulation of PTGS2, MMP1, and VCAM1. This provides some theoretical basis to treat IPF with this compound and indicates that a combination study is beneficial for revealing drug mechanisms.

PMID:41926303 | DOI:10.2174/0115734099433388260204214424

Cancer Immunol Immunother. 2026 Apr 2;75(4):131. doi: 10.1007/s00262-026-04374-3.

ABSTRACT

Immunotherapy has revolutionized cancer treatment, yet characterizing the spatial complexity of the tumor immune microenvironment remains a challenge. In this study, we established a comprehensive computational framework integrating multi-omics profiling across 27 cancer types to decode immune-related non-coding RNA regulatory networks. Moving beyond traditional bulk analysis, we utilized spatial transcriptomics to dissect the spatial localization of these regulators. We identified the SNHG6-BIRC5 axis as a critical driver of the "immune-cold" phenotype in lung adenocarcinoma. We provide visual evidence that this axis localizes to tumor nests and negatively correlates with T- cell infiltration, elucidating a mechanism of spatial immune exclusion. Validating the clinical relevance of these findings, genome-scale CRISPR-Cas9 screening data confirmed the functional essentiality of these targets for cancer cell survival. Furthermore, pharmacogenomic analysis revealed that high expression of this axis correlates with sensitivity to chemotherapy agents like Vinblastine, suggesting a potential stratification strategy for patients with immune-excluded tumors. To expand the clinical utility to immunotherapy prediction, we developed a pan-cancer XGBoost machine learning model incorporating 14 high-performance regulatory features. This model achieved robust performance in distinguishing immunotherapy responders from non-responders with an AUC of 0.771, outperforming traditional markers such as PD-L1. Collectively, this study highlights spatial determinants of immune exclusion and chemotherapy sensitivity- and presents a generalized machine- learning tool for precision immunotherapy stratification. The developed online resource is freely available to facilitate community-wide biomarker discovery.

PMID:41925746 | PMC:PMC13046951 | DOI:10.1007/s00262-026-04374-3

Mucosal Immunol. 2026 Mar 30:S1933-0219(26)00036-X. doi: 10.1016/j.mucimm.2026.03.012. Online ahead of print.

ABSTRACT

Aberrant inflammation and structural lung damage occurs early in life for people with cystic fibrosis (CF). Even in the era of CFTR modulators, anti-inflammatory therapy may still be needed to prevent establishment and lifelong consequences of bronchiectasis. In this study, we integrated transcriptome-wide single-cell RNA sequencing data and highly multiplexed surface protein expression to create the largest comprehensive paediatric lower airway atlas of >190,000 cells from 45 bronchoalveolar lavage (BAL) samples resulting in 43 immune and epithelial cell populations, all available for exploration on CELLxGENE. We then investigated inflammatory cell responses in children with CF to show widespread gene expression dysregulation of macrophage populations in the preschool CF lung. This included alterations in pathways associated with TNF and IFN signalling, cholesterol homeostasis, as well as pulmonary fibrosis, that were further altered by the early development of bronchiectasis. We showed that the CFTR modulator ivacaftor restores some of these macrophage-related functional deficits and reduces expression of pathways associated with neutrophil infiltration, however the modulator lumacaftor/ivacaftor did not result in any detectable changes in transcriptional response. This work represents a comprehensive, multi-omic single-cell analysis of BAL from preschool children and the results may inform the future development of anti-inflammatory therapy for children with CF.

PMID:41921915 | DOI:10.1016/j.mucimm.2026.03.012

Environ Int. 2026 Mar 28;210:110212. doi: 10.1016/j.envint.2026.110212. Online ahead of print.

ABSTRACT

Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental contaminants, raising concerns about their potential to cause inflammation, oxidative stress, and lung injury through respiratory toxicity. Due to their smaller size, larger surface area, and greater reactivity, NPs may pose a greater risk than MPs, yet size-dependent toxicity mechanisms remain unclear. This study investigates the distinct early molecular initiating events and toxicological effects of 1 μm polystyrene MPs (PS-MPs) and 20 nm polystyrene NPs (PS-NPs). Based on the internal exposure dose estimated from Py-GC/MS analysis, in vitro exposure concentrations were set at 0, 62.5, 125, 250, 500, and 1000 μg/mL. Multi-omics sequencing and integrative analysis identify specific proteomic and metabolomic alterations. Molecular dynamics simulations and co-immunoprecipitation assays elucidate binding interactions between PS-NPs-induced proteins and metabolic enzymes. In vitro and in vivo experiments reveal a greater accumulation of PS-NPs through endocytosis compared to PS-MPs; while pronounced histopathological damage with inflammatory response in mice lungs were only induced by PS-NPs, rather than PS-MPs. Compared to control group, PS-MPs partly caused proteomic or metabolomic perturbations, while PS-NPs induced significant differential expression of more extensive proteins and metabolites. PS-NPs exposure specifically upregulates insulin-like growth factor 2 receptor (IGF2R) expression and reduces Hypoxanthine levels when compared with PS-MPs. IGF2R directly interacts with Hypoxanthine-guanine phosphoribosyl transferase (HPRT), a key enzyme in Hypoxanthine metabolism, causing its disruption. This study provides important insights into the comparative toxic effects between PS-NPs with PS-MPs, especially the unique toxicological mechanisms of PS-NPs, thereby advancing the understanding of airborne plastic pollutant risks and supporting future regulatory assessments.

PMID:41921402 | DOI:10.1016/j.envint.2026.110212

Front Immunol. 2026 Mar 16;17:1822612. doi: 10.3389/fimmu.2026.1822612. eCollection 2026.

ABSTRACT

[This corrects the article DOI: 10.3389/fimmu.2026.1782545.].

PMID:41918731 | PMC:PMC13033988 | DOI:10.3389/fimmu.2026.1822612

Front Pediatr. 2026 Mar 16;14:1770578. doi: 10.3389/fped.2026.1770578. eCollection 2026.

ABSTRACT

The neonatal lung, once considered sterile, is now recognized to harbor a dynamic and complex microbiome that plays a critical role in respiratory health and disease. This review synthesizes current evidence on the composition, development, and functional impact of the lung microbiome in neonates, with a focus on its involvement in key respiratory disorders such as bronchopulmonary dysplasia, respiratory syncytial virus infection, neonatal acute respiratory distress syndrome, cystic fibrosis, and asthma predisposition. We place particular emphasis on the bidirectional communication along the gut-lung axis as a central mechanism, wherein intestinal microbiota and their metabolites modulate pulmonary immunity and inflammation. Emerging multi-omics studies that integrate microbial data with host metabolomic and immune profiles are highlighted for their role in deciphering disease-specific dysbiotic signatures and mechanistic pathways. Critically, this review advances the discussion beyond association by evaluating the translational potential of the microbiome as both a diagnostic biomarker and a therapeutic target. We provide a critical appraisal of innovative microbiome-targeted strategies-including probiotics, postbiotics, phage therapy, and bacterial lysates-and discuss the unique challenges and future directions for translating these approaches into safe, effective clinical interventions for vulnerable neonates. By bridging foundational science with clinical implications, this work aims to inform the development of novel, ecology-informed therapeutics to prevent and mitigate neonatal respiratory diseases.

PMID:41918694 | PMC:PMC13033698 | DOI:10.3389/fped.2026.1770578

Cancer Immunol Immunother. 2026 Mar 31;75(4):126. doi: 10.1007/s00262-026-04368-1.

ABSTRACT

While anti-programmed death-1 (anti-PD-1) therapy has revolutionized lung cancer treatment, its efficacy remains limited by an immunosuppressive tumor microenvironment (TME). We therefore investigated whether combining anti-PD-1 inhibitor with catgut embedding at the Zusanli acupoint (CIAA) could enhance anti-tumor immunity by reprogramming the TME in a lung cancer mouse model. Combining in vivo tumor monitoring, multi-parametric immune profiling (flow cytometry, IHC, ELISA), and multi-omics analyses (transcriptomics and metabolomics), we found that the combination therapy was associated with enhanced tumor growth inhibition. This effect correlated with a comprehensive TME transformation: conversion to an immunologically active state with increased effector immune cell infiltration (CD8⁺ T, CD4⁺ T, B cells, macrophages) and decreased regulatory T cells, coupled with suppression of pro-tumorigenic factors (VEGF, IL-6). Integrated omics analysis suggests that the combined treatment may modulate tumor-stroma interaction pathways (e.g., PI3K-Akt, focal adhesion) and rewire immunometabolic networks (e.g., tryptophan metabolism). Our study provides hypothesis-generating correlative data positioning CIAA as a potential adjunct capable of remodeling the TME to potentiate anti-PD-1 therapy in lung cancer.

PMID:41915222 | PMC:PMC13038699 | DOI:10.1007/s00262-026-04368-1

Zhonghua Yi Xue Za Zhi. 2026 Mar 31;106:1-7. doi: 10.3760/cma.j.cn112137-20251201-03143. Online ahead of print.

ABSTRACT

Objective: To analyze the association between molecular typing and prognosis with recurrence pattern in triple-negative breast cancer (TNBC) patients based on long-term follow-up of a multi-omics cohort. Methods: A retrospective analysis was performed on the clinical data and transcriptomic data of patients diagnosed with TNBC at Department of Breast Surgery, Fudan University Shanghai Cancer Center from January 1, 2007, to December 31, 2014. The survival status of patients was documented, and the follow-up continued until the patients' death or August 31, 2025. According to the"Fudan subtype", the patients were categorized into the basal-like immune suppressed (BLIS), immunomodulatory (IM), luminal androgen receptor (LAR), and mesenchymal-like (MES). Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was employed to evaluate the differences in overall survival (OS), disease-free survival (DFS) and recurrence-free interval (RFI) among TNBC patients with different molecular subtypes. Multivariate Cox proportional hazards regression analysis was used to assess the association between"Fudan subtype"and OS, DFS and RFI. Differential expression analysis and subsequent gene set enrichment were conducted. Competing-risk models were used to calculate the cumulative incidence of lung metastasis after accounting for competing events, and the differences were assessed using the Fine-Gray test. Results: After excluding 9 patients lost to follow-up, a total of 351 patients with TNBC were included in the analysis. The mean age at baseline was 53.46±11.36 years, and the median follow-up duration was 102.09 months. During follow-up, 72 patients died and 84 experienced recurrence or metastasis. Among them, 134 patients were classified as the BLIS subtype, with 27 deaths (20.15%); 86 patients were classified as the IM subtype, with 11 deaths (12.79%); 81 patients were classified as the LAR subtype, with 22 deaths (27.16%); and 50 patients were classified as the MES subtype, with 12 deaths (24.00%). The 10-year RFI rates for the BLIS, IM, LAR, and MES subtypes were 80.12% (95%CI: 73.41%-87.44%), 92.35% (95%CI: 86.64%-98.43%), 81.92% (95%CI: 73.39%-91.44%), and 72.95% (95%CI: 61.37%-86.71%), respectively. Kaplan-Meier survival curves showed that the differences of RFI among the four molecular subtypes of patients were statistically significant (P=0.040). Multivariate analysis showed that LAR subtype (LAR vs IM, HR=2.41, P=0.042) was the independent risk factor for DFS, and BLIS subtype (BLIS vs IM, HR=4.17, P=0.011), LAR subtype (LAR vs IM, HR=3.49, P=0.040) and MES subtype (MES vs IM, HR=3.98, P=0.019) were independent risk factors for RFI. The BLIS subtype is more likely to develop recurrence or metastasis in the early postoperative period, particularly lung metastasis. Differential gene expression analysis showed that BLIS subtype-specific genes, including those involved in proliferation and cell cycle activity, were predominantly upregulated in tumors with early recurrence or metastasis. Competing-risk analysis demonstrated that BLIS patients had a higher cumulative incidence of lung metastasis both overall and within the first 5 years after surgery compared with non-BLIS patients (both P<0.05). Conclusion: The"Fudan subtype"was significantly associated with RFI in early-stage TNBC patients. In addition, recurrence and metastasis were more likely to be observed in the early postoperative period in the BLIS subtype, particularly early lung metastasis.

PMID:41913624 | DOI:10.3760/cma.j.cn112137-20251201-03143

EMBO Mol Med. 2026 Mar 30. doi: 10.1038/s44321-026-00410-y. Online ahead of print.

ABSTRACT

Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.

PMID:41912871 | DOI:10.1038/s44321-026-00410-y

Cancer Lett. 2026 Mar 28;648:218465. doi: 10.1016/j.canlet.2026.218465. Online ahead of print.

ABSTRACT

Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of scalable cross-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, within specific lineages. By analyzing multi-omics data encompassing 39 HOX genes across more than 80,000 RNA-seq samples across 23 cancer types spanning 114 cancer subtypes, we found that HOX code expression robustly stratifies lineage-constrained and lineage-plastic states at a cross-cancer level. This framework revealed previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying distinct HOX code divergence compared to non-plastic counterparts. Differential expression analysis across these representative malignancies identified RUNX1T1 as a consistent regulator associated with HOX-defined plastic states. We validated RUNX1T1 upregulation in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and demonstrated that RUNX1T1 is functionally required for lineage-plastic programs in prostate cancer models. AI-based structural modeling and co-immunoprecipitation established the NCOR/HDAC3 complex as a critical binding partner of RUNX1T1. CUT&RUN profiling revealed that RUNX1T1 remodels chromatin by globally reducing active enhancer marks, thereby repressing lineage-defining differentiation programs and reshaping HOX positional identity. Selective pharmacologic inhibition of HDAC3 or targeted gene silencing via lipid nanoparticles suppressed the growth of lineage-plastic cancer cells, uncovering a therapeutically actionable vulnerability. Together, these findings establish RUNX1T1 as a cross-lineage regulator of HOX code-defined plasticity and identify the RUNX1T1-HDAC axis as a targetable mechanism underlying cancer lineage plasticity.

PMID:41912135 | DOI:10.1016/j.canlet.2026.218465

Microb Pathog. 2026 Mar 28;215:108464. doi: 10.1016/j.micpath.2026.108464. Online ahead of print.

ABSTRACT

Despite the clinical application of Ophiopogon japonicus in idiopathic pulmonary fibrosis (PF), its key anti-fibrotic components and underlying mechanisms remain poorly defined. Using a bleomycin-induced murine PF model, we systematically compared the efficacy of the total extract (OJTE), polysaccharides (OJTP), saponins (OJTS), and flavonoids (OJTF). The active component was further investigated via integrated metagenomics and metabolomics (serum/feces) to decipher the gut-lung axis mechanism. All O. japonicus components attenuated lung injury and collagen deposition, with OJTP demonstrating the most potent efficacy (reducing lung hydroxyproline content by 42.12% (p < 0.01) compared to the model group). Multi-omics analysis revealed that OJTP remodeled the gut microbiota, notably enriching probiotic strains such as Muribaculaceae bacterium (log₂FC = 2.17) and Duncaniella muricolitica (log₂FC = 2.06), as well as the polysaccharide-utilizing species Prevotella sp. MGM2 (log₂FC = 2.79). Concomitantly, OJTP significantly altered host metabolism, upregulating key metabolites including urobilinogen (p < 0.0001) and 5-amino valeric acid betaine (5-AVAB, p < 0.002). These metabolites are implicated in porphyrin and amino acid metabolism, respectively. Correlation networks further established strong associations between these OJTP-modulated microbes and metabolites. Our study first identifies OJTP as the primary bioactive component of O. japonicus against PF. We propose a novel trans-organ mechanism wherein OJTP ameliorates PF via orchestrating a "gut microbiota-metabolite" axis, highlighting the therapeutic potential of targeting polysaccharide-probiotic synergy.

PMID:41912071 | DOI:10.1016/j.micpath.2026.108464

J Vis Exp. 2026 Mar 13;(229). doi: 10.3791/70383.

ABSTRACT

This study utilized a multi-omics and computational biology framework to investigate the therapeutic potential of the Traditional Chinese Medicine (TCM) formula Buti Huatan Tang (BTHTT) against chronic obstructive pulmonary disease (COPD). Significant physiological improvements were observed in a rat model following BTHTT intervention. Histological analysis showed a reversal of lung pathological damage, while biochemical assays, and transcriptomics confirmed the normalization of IL-1β and IL-1R2 levels. Additionally, metabolic profiling revealed that BTHTT corrected disruptions in T3 and T4 thyroid hormone levels. A negative correlation was observed between the IL-1β/IL-1R2 axis and these thyroid hormones, indicating that their regulation is associated with the formula's therapeutic effect. Beyond direct measurements, machine learning algorithms identified ten COPD signature genes from clinical databases. Pathway enrichment analysis suggests that BTHTT may act through cytokine-cytokine-receptor interactions and thyroid hormone synthesis pathways. Furthermore, while 283 components were identified in vivo, compounds such as tanshinone IIA and cryptotanshinone are currently considered candidate active substances. Their role as primary drivers is supported by a model in which they stably bind to IL-1R2; this inference is based on molecular docking and molecular dynamics (MD) simulations rather than direct experimental isolation. Overall, the data support a model in which BTHTT exerts a multi-target effect on COPD by modulating inflammation and metabolic homeostasis. This integrated approach provides a refined scientific basis for the clinical application of BTHTT and highlights specific pathways for future experimental validation.

PMID:41911070 | DOI:10.3791/70383

Front Immunol. 2026 Mar 13;17:1770348. doi: 10.3389/fimmu.2026.1770348. eCollection 2026.

ABSTRACT

Interstitial lung disease (ILD) is one of the most common extra-articular manifestations of rheumatoid arthritis (RA). Some patients with RA-ILD may develop progressive pulmonary fibrosis, leading to severe impairment of lung function and respiratory failure, which impacts quality of life and can even be life-threatening. This review identified genetic susceptibility, environmental factors, and immune dysregulation as key contributors to the etiology and pathogenesis of RA-ILD. We highlight that autoantibodies, adaptive immune abnormalities, and tertiary lymphoid organ formation significantly drive pulmonary inflammation and fibrosis, while pro-inflammatory cytokines and epithelial-mesenchymal transition (EMT) further contribute to lung tissue injury. Current treatment options, including glucocorticoids, immunosuppressants, and antifibrotic agents such as nintedanib and pirfenidone, are often limited by substantial side effects. Additionally, emerging therapies like JAK inhibitors, CAR-T cells, and the upcoming phosphodiesterase-4B inhibitor, nerandomilast, show promise, but no curative treatment exists to date. Future research could focus on multi-omics technologies and conducting multicenter clinical trials to establish therapeutic targets and advance precision medicine for RA-ILD.

PMID:41909710 | PMC:PMC13021622 | DOI:10.3389/fimmu.2026.1770348

J Ethnopharmacol. 2026 Mar 26;365:121591. doi: 10.1016/j.jep.2026.121591. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) lacks effective therapies. HIF-1α-driven glycolysis can promote histone lactylation and sustain pro-inflammatory (M1) macrophage responses. Daxiefei Decoction (DXFD), a classic traditional Chinese medicine formula, is used for pulmonary inflammatory diseases, but its immunometabolic mechanism remains unclear.

AIM OF THE STUDY: To evaluate the protective efficacy of DXFD against lipopolysaccharide (LPS)-induced ALI and to determine whether it acts through the HIF-1α/glycolysis/histone H3K18 lactylation (H3K18la) axis to regulate macrophage polarization.

MATERIALS & METHODS: DXFD constituents were characterized by UPLC-LTQ-Orbitrap-MS/MS, followed by network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Lung transcriptomics and metabolomics were performed in ALI mice. Efficacy and mechanisms were assessed in LPS-challenged mice and RAW264.7 macrophages using histopathology, ELISA, qRT-PCR, Western blotting, and immunofluorescence. HIF-1α overexpression was used for validation.

RESULTS: DXFD dose-dependently alleviated lung injury and reduced pro-inflammatory cytokines in vivo, and suppressed M1 polarization in vivo and in LPS-stimulated macrophages. Multi-omics indicated activation of HIF-1α-associated inflammatory and glycolytic programs in ALI, which were normalized by DXFD. DXFD decreased glycolytic enzyme expression and reduced histone H3K18 lactylation (H3K18la); these effects were partially reversed by HIF-1α overexpression. Molecular docking and dynamics suggested stable binding of baicalin to HIF-1α.

CONCLUSIONS: DXFD mitigates ALI by dampening HIF-1α-dependent glycolysis and H3K18la, thereby restraining M1-driven inflammatory amplification.

PMID:41903585 | DOI:10.1016/j.jep.2026.121591